HB Lecture 3

Which single Y-linked gene triggers testis development in mammals?

SRY

SRY sits in a small region at which part of the Y chromosome?

The tip of the short arm, just beyond the pseudoautosomal region (PAR)

X and Y chromosomes descend from [____1]; over evolution the Y has progressively [____2].

1) a common ancestral chromosome pair; 2) eroded in size

In the early embryo, SRY first acts on which gonadal cell type?

Sertoli cells

SRY acts on [____1] cells in the early embryo, which switches on steroid-producing [____2] cells.

1) Sertoli; 2) Leydig

Which cell type of the adult testis produces androgens?

Leydig cells

Which cell type of the seminiferous tubule supports developing germ cells (the "nurse" cells)?

Sertoli cells

Sertoli cells secrete substances that initiate which germ-cell process?

Meiosis

Sertoli cells concentrate testosterone locally using which protein?

Androgen-binding protein

Which Sertoli cell product prevents formation of the female oviduct?

Anti-Müllerian hormone (AMH)

Which structure, built from tight junctions between Sertoli cells, protects spermatids from the immune system?

The blood-testis barrier (BTB)

Which molecule is the preferred energy source of spermatocytes and spermatids, and which cell supplies it?

Lactate, produced by Sertoli cells

Length of one seminiferous tubule: [____1]. Combined length in one human testis: [____2].

1) ~30–80 cm; 2) ~600–900 m

Which organelle fills the mid-piece of a mature sperm, and what is its role?

Mitochondria; they supply energy to the tail

The developing testis secretes two products that shape the internal ducts. Name them and the duct each acts on.

Testosterone stimulates the Wolffian duct; AMH causes Müllerian duct degeneration

Which embryonic duct gives rise to the vas deferens?

Wolffian duct

What does AMH do to the Müllerian duct, and what is the resulting anatomical outcome?

Causes it to degenerate, so no uterus forms

What class of molecule is AMH?

A large peptide/glycoprotein of the TGF-β superfamily

Alternative names for AMH used in the lecture?

Müllerian inhibiting hormone (MIH) / Müllerian inhibitory factor

With no SRY and no testis, the [____1] duct degenerates and the [____2] duct persists (forming oviduct and uterus).

1) Wolffian; 2) Müllerian

Jost's classic experiment: a piece of fetal testis was grafted against one ovary of a rabbit fetus. What happened on that side?

Wolffian duct stimulated and Müllerian duct inhibited

In Jost's graft experiment, what did the effect NOT do, and what does this show?

It did not extend to the other side of the body; testis action on the ducts is local

Later experiments used local crystalline implants of testosterone. What was the result?

Wolffian duct stimulated, but Müllerian duct remained (testosterone alone does not cause Müllerian regression; AMH is needed)

State the original Jost hypothesis.

Androgens plus AMH secreted by fetal testes at critical stages account for the full range of sexually dimorphic urogenital traits seen at birth

Jost's hypothesis was later expanded to cover what additional areas?

Sexual differentiation of the brain and behaviour

In human fetal development, which becomes active first (approx. weeks, read from graph): Sertoli or Leydig activity?

Sertoli (~week 7), then Leydig (~week 8)

Approximately when does human fetal serum testosterone peak (read from graph)?

~Weeks 11–12 of gestation

Approximately when does male external genital differentiation occur in humans (read from graph)?

~Weeks 10–13

Which receptor mediates testosterone and DHT action, and what family does it belong to?

Androgen receptor (NR3C4); nuclear hormone receptor family; binds DNA directly

Which enzyme converts testosterone to dihydrotestosterone (DHT)?

5α-reductase

Testosterone and DHT bind the same receptor. Which has higher affinity?

DHT

Name actions mediated by testosterone itself via the androgen receptor.

Wolffian duct stimulation, spermatogenesis, gonadotrophin regulation (and testicular descent)

Name actions mediated mainly by DHT.

External virilization and maturation at puberty (development of male external genitalia)

Which enzyme converts testosterone to oestradiol-17β, and what is its developmental role?

Aromatase; sexual differentiation of the brain

In the lifetime testosterone profile, the early peak drives [____1], the perinatal peak drives [____2], and the pubertal rise drives [____3].

1) gonad/sexual differentiation; 2) establishment of the sexually dimorphic brain; 3) secondary sex characteristics

Danazol is used to treat which condition, and why is it dangerous in pregnancy?

Endometriosis; it is androgenic and can virilize a genetic female fetus

List the features of an XY castrate shown in the lecture.

Scant pubic and body hair, small penis, continued long-bone growth (lack of androgen effect on bone growth)

What did the Korean eunuch lifespan study (Min et al., 2012) conclude?

Eunuchs lived longer; male sex hormones decrease lifespan in men

Klinefelter's syndrome: karyotype?

XXY

Klinefelter's gonadal features?

Small testes, low testosterone production, no spermatozoa

Why are no spermatozoa produced in Klinefelter's syndrome?

XXY germ cells cannot survive in the testicular environment

Klinefelter's duct and genital status?

Müllerian duct absent, Wolffian duct present, penis developed

Klinefelter's other features?

Limited breast development and scant body hair

Klinefelter's management?

No cure; symptom management; assisted reproduction such as testicular sperm extraction

Swyer syndrome (XY gonadal dysgenesis): karyotype and a known genetic cause?

46,XY; mutations in SRY (~15% of cases)

Swyer syndrome gonads?

No testis develops; ovaries develop then degenerate (streak gonads)

Swyer syndrome: status of uterus and vagina, and menstruation?

Uterus and vagina normal, but no menstruation

Swyer syndrome: hormonal and pubertal features?

No sex steroids, no pubic hair, no breast development, no puberty, tall stature

Swyer syndrome: key risk and management?

High risk of gonadal cancer; HRT to induce female puberty, gonadectomy, ART possible if uterus can develop

Androgen insensitivity syndrome (AIS) has what two other names?

Morris syndrome; testicular feminisation syndrome

What is the molecular defect in AIS?

Lack of androgen receptor, so the body cannot perceive testosterone

Why do breasts develop in AIS?

Testicular oestrogen drives breast development with no testosterone signal to oppose it

Why is no uterus present in AIS?

The testis still produces AMH

Why do the testes fail to descend in AIS?

Descent depends on a testosterone signal

Vagina in AIS?

Short and blind-ending

AIS management?

Multidisciplinary: HRT, gonadectomy to prevent tumours, orchiopexy, counselling (depends on partial vs complete AIS)

AIS individuals have intact aromatase and no overt masculine behaviour. What does this suggest about humans?

Testosterone aromatisation may not be important for gender identity in humans (contrast with rodents)

46,XX testicular DSD (de la Chapelle syndrome): how does it arise?

An X from the father carries SRY, attached by crossover during meiosis in spermatocytes/spermatids

46,XX testicular DSD (de la Chapelle): phenotype?

Typical male phenotype, small external genitalia, gynecomastia, often sterile (azoospermia)

46,XX testicular DSD (de la Chapelle): treatment?

HRT (testosterone, GH), genital reconstruction surgery, counselling; no cure for infertility

Turner's syndrome: karyotype and gonads?

XO (one X missing or partially missing); ovaries or streak gonads with no germ cells and no steroids

Turner's syndrome: which ducts are present and why?

Müllerian present (no testis, so no AMH); Wolffian absent (no testosterone)

Turner's syndrome: other physical features?

Shorter stature, thickened neck, little breast development (no sex steroids); mental health issues

Turner's syndrome treatment?

HRT (oestrogen, progesterone, GH); egg donation/IVF possible if a uterus is present

XX germ cells survive in which gonadal environment?

Ovarian

XO germ cells fail to survive in an ovary. What does this imply about X dosage?

An X-linked dosage mechanism is required for female germ cell survival

Which karyotypes' germ cells die in the testicular environment?

XX and XXY

Guevedoces: which enzyme deficiency causes the condition?

5α-reductase-2 deficiency (cannot synthesise DHT)

Guevedoces: what happens at puberty after being raised as girls?

Testosterone rises enough to virilize the body; testes descend; penis develops and grows

Guevedoces: meaning of the name and the alternative local name?

"Penis at 12"; machihembras ("first women, then men")

Guevedoces: who investigated the Dominican Republic village in the early 1970s?

Dr Julianne Imperato (Cornell endocrinologist)

Guevedoces: where else besides the Dominican Republic are such communities found?

Turkey and New Guinea (isolated communities)

According to the lecture, how is "sex" defined and when is it fixed?

By gamete production (females make eggs and bear progeny; males make sperm); determined during development and cannot truly be changed currently

[APPLICATION] A newborn with a 46,XY karyotype has female external genitalia, a short blind-ending vagina, no uterus and undescended testes. At puberty she develops breasts and is tall. Name the condition, the defect, and explain the absent uterus and the breast development.

Androgen insensitivity syndrome; absent androgen receptor. No uterus because testes secrete AMH. Breasts develop because testicular oestrogen is unopposed by androgen signalling

[APPLICATION] A 16-year-old with female appearance has primary amenorrhoea, no breast development, no pubic hair and tall stature. Imaging shows a normal uterus and vagina and streak gonads; karyotype is 46,XY. Diagnosis and why is a uterus present?

Swyer syndrome (XY gonadal dysgenesis), e.g. SRY mutation. No testis means no AMH, so Müllerian duct persists

[APPLICATION] A 15-year-old girl has short stature, a thickened neck, no menstruation and little breast development. Karyotype is 45,X. Why are Müllerian structures present but Wolffian structures absent?

Turner's syndrome. No testis, so no AMH (Müllerian persists) and no testosterone (Wolffian not maintained)

[APPLICATION] A 45,X patient asks about having a child. What is possible and what must be present?

Egg donation/IVF is possible, provided a uterus is present; HRT supports development

[APPLICATION] A tall man has small testes, gynecomastia, scant body hair and azoospermia. Karyotype is 47,XXY. Why is there no sperm, and what fertility option exists?

Klinefelter's syndrome. XXY germ cells cannot survive in the testis. Testicular sperm extraction (ART) is an option; there is no cure

[APPLICATION] A phenotypically male patient has small external genitalia, gynecomastia and azoospermia. Karyotype is 46,XX but PCR is SRY-positive. Explain the mechanism.

46,XX testicular DSD (de la Chapelle syndrome). Paternal crossover during meiosis attached SRY to an X chromosome

[APPLICATION] A child in an isolated Dominican village is raised as a girl, then at puberty the testes descend and a penis grows. Which enzyme is deficient and why do the external genitalia look female at birth?

5α-reductase-2 deficiency. Cannot make DHT, which drives external virilization; Wolffian duct development (testosterone-dependent) is unaffected; testosterone rise at puberty then virilizes

[APPLICATION] A genetic female is born with externally virilized genitalia. Her mother took danazol for endometriosis during pregnancy. Explain.

Danazol is androgenic; fetal exposure to androgens virilizes the external genitalia in a genetic female

[APPLICATION] Crystalline testosterone is implanted beside the ovary of a fetal rabbit. Predict the effect on the Wolffian and Müllerian ducts.

Wolffian duct is stimulated locally, but the Müllerian duct remains, since AMH (not testosterone) causes its regression

[APPLICATION] A 46,XY fetus is given a 5α-reductase inhibitor. Which structures are affected, and which are spared?

External genitalia development (DHT-dependent) is impaired; testosterone-dependent Wolffian duct stimulation is spared

[APPLICATION] In an XY embryo, SRY is non-functional. Predict gonad, ducts, and hormones.

No Sertoli differentiation, no Leydig cells, no testosterone or AMH; default female pathway (Müllerian persists, Wolffian degenerates)

[APPLICATION] In an XY fetus with normal Leydig cells, the Sertoli cells cannot release AMH. What happens to the Müllerian duct?

It persists, so oviduct/uterus structures form alongside the testis and Wolffian derivatives

[APPLICATION] An XY fetus has functioning Sertoli cells but no Leydig cell steroid production. What happens to each duct?

Müllerian duct regresses (AMH present); Wolffian duct is not stimulated (no testosterone)

[APPLICATION] A man has a breach in the blood-testis barrier. Which cells are at risk and why?

Developing spermatids/germ cells are exposed to the immune system and can be attacked

[APPLICATION] A boy is castrated before puberty. Predict stature, penis size and body hair.

Continued long-bone growth (taller), small penis, scant pubic and body hair, due to lack of androgens

[APPLICATION] A male neonatal rodent is given an aromatase inhibitor. Which process is expected to be disrupted?

Sexual differentiation of the brain (testosterone must be aromatised to oestradiol)

[APPLICATION] An XY individual lacks the androgen receptor but has intact aromatase, is raised as a girl and identifies as a woman. What does this suggest?

Testosterone aromatisation may not drive gender identity in humans, in contrast to rodents; also upbringing vs brain remains an open question

[APPLICATION] Two 46,XY individuals both have female appearance. One has a uterus and no breasts; the other has no uterus and well-developed breasts. Which is Swyer and which is AIS?

Uterus and no breasts = Swyer (no AMH, no steroids). No uterus and breasts = AIS (AMH present, testicular oestrogen unopposed)

[APPLICATION] A patient with complete AIS has intra-abdominal testes. Name two management options.

Gonadectomy to prevent tumours, and/or HRT; orchiopexy and counselling are also options depending on partial vs complete AIS